Cytochrome c Release and Apoptosis Induced by Mitochondrial Targeting of Nuclear Orphan Receptor TR3

Li, Hui; Kolluri, Siva Kumar; Gu, Jingmin; Dawson, Marcia I.; Cao, Xihua; Hobbs, Peter D.; Lin, Bingzhen; Chen, Guo-quen; Lu, Jiang-song; Lin, Feng; Xie, Zhihua; Fontana, Joseph A.; Reed, John C.; Zhang, Xiaokun

doi:10.1126/science.289.5482.1159

Cited by 605 publications

(668 citation statements)

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“…32,36 CD437 has been suggested to induce apoptosis by directly targeting mitochondria, 37 although nuclear export of the orphan receptor nur77 and relocation to the mitochondria has also been indicated to mediate CD437-induced apoptosis. 38 We have previously shown that agonist RRMs induce a strong and sustained activation of stress kinases JNK and p38, which correlates with the induction of apoptosis. 39 JNK is necessary for the release of cytochrome c during stressinduced apoptosis 40 and is known to phosphorylate Bcl-2 and Bcl-X L , hindering their antiapoptotic function.…”

Section: Introductionmentioning

confidence: 93%

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

López-Hernández¹,

Ortiz²,

Bayón³

et al. 2003

Cell Death Differ

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Certain retinoid-related molecules (RRMs) with agonist or antagonist activities have been described to induce apoptosis in a variety of cancer cell lines and show promise for the treatment of cancer. Similar to other chemotherapeutic drugs, these retinoid analogs have been suggested to induce apoptosis through the intrinsic pathway, which requires the release of cytochrome c from the mitochondria for the effective activation of caspase 9. Expression of a catalytically inactive form of caspase 9, which functions as a dominant negative mutant, inhibits the induction of DEVDase activity and nuclear fragmentation by selective RRMs. Whereas the RRMs could induce the release of cytochrome c in the absence of caspase 9 activity, the later is necessary for the effective release of Smac/Diablo from the mitochondria. Furthermore, overexpression of Bcl-2 or Bcl-X L also inhibits RRM-induced apoptosis. We demonstrate that activation of caspase 2 by the agonist MX2870-1 requires caspase 9 activity and is inhibited by Bcl-2 overexpression. In contrast, the antagonist MX781 induces cleavage of procaspase 2 upstream of mitochondria and independently of caspase 9. Thus, two retinoid analogs with unique characteristics activate two distinct apical caspases (2 or 9) to initiate apoptosis. In addition to caspase-mediated cell death, sustained exposure to the RRMs can also lead to loss of cell viability in cells lacking caspase 9 activity or in cells stimulated in the presence of the caspase inhibitor Z-VADfmk. Moreover, MX2870-1 and MX781 produce cell cycle arrest independently of caspase activity and the retinoid receptors.

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Section: Introductionmentioning

confidence: 93%

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

López-Hernández¹,

Ortiz²,

Bayón³

et al. 2003

Cell Death Differ

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show abstract

Section: Introductionmentioning

confidence: 99%

“…Nur77 expression is rapidly induced during apoptosis of immature thymocytes, T-cell hybridomas and various cancer cell types (Liu et al, 1994;Woronicz et al, 1994;Li et al, 1998Li et al, , 2000Milbrandt, 1988;Uemura and Chang, 1998). We have previously demonstrated a new paradigm in cancer cell apoptosis, in which Nur77 is induced, then translocates from the nucleus to the mitochondria, leading to release of cytochrome c from the mitochondria (Li et al, 2000). The apoptosis-associated nuclear egress of Nur77 has been observed in cancer cells from the lung, ovary, colon, stomach and breast (Dawson et al, 2001;Holmes et al, 2002Holmes et al, , 2003Liu et al, 2002;Wu et al, 2002;Jeong et al, 2003;Kolluri et al, 2003;Wilson et al, 2003;Cao et al, 2004;Jacobs et al, 2004;Lin et al, 2004;Lee et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…The Nur77-dependent apoptotic process is triggered by a number of apoptosis inducers, including retinoidrelated molecule 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecar-boxylic acid (AHPN) (also called CD437) (Li et al, 2000) and its analogs (Li et al, 2000;Dawson et al, 2001;Holmes et al, 2002Holmes et al, , 2003Kolluri et al, 2003;Cao et al, 2004;Lin et al, 2004), etoposide (Li et al, 2000;Liu et al, 2002;Wilson et al, 2003), and insulin-like growth factor binding protein-3 (Lee et al, 2005). The importance of Nur77-dependent apoptotic pathway in mediating the anticancer activity of chemotherapeutic agents is supported by the positive correlation between Nur77 family member Nor-1 expression and survival in diffuse large B-cell lymphoma patients treated with therapeutic drugs (Shipp et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Nur77 mitochondrial targeting is induced by apoptotic retinoid-related compounds, TPA, a calcium ionophore, and chemotherapeutic agents, which are known to act through membrane-signaling pathways involving various kinases and phosphatases (Li et al, 2000;Kolluri et al, 2003). Thus, phosphorylation may play a role in regulating Nur77 subcellular trafficking.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

et al. 2006

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Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/ CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.

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Retinoids

Leid¹

2003

Burger's Medicinal Chemistry and Drug Discovery

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Derivatives of vitamin A, collectively known as retinoids, play key roles in development, cellular differentiation, vision, and reproduction. Retinoids are now well established as valuable therapeutic agents in the treatment of a variety of skin and proliferative disorders. This chapter covers the biosynthesis and metabolism of naturally occurring retinoids, the role of these retinoids in the visual cycle, and the clinical usefulness and adverse effects of retinoids and synthetic derivatives in the treatment of disease.

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Cytochrome c Release and Apoptosis Induced by Mitochondrial Targeting of Nuclear Orphan Receptor TR3

Cited by 605 publications

References 37 publications

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

Retinoids

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